Research Summary

Semaglutide Associated With Largest Weight Reduction in Patients With Schizophrenia Spectrum Disorders Receiving Antipsychotics

Edited by:
Ashton L. Stahl

Key Highlights

  • The review included 95 randomized clinical trials, 39 pharmacological interventions, and 5,898 participants.
  • Semaglutide produced the largest weight reduction compared with placebo: −10.98 kg.
  • Liraglutide, topiramate, metformin, and exenatide also significantly reduced body weight.
  • Semaglutide and metformin were associated with clinically meaningful weight reductions of at least 5%.

Semaglutide, liraglutide, topiramate, metformin, and exenatide were associated with the greatest weight reductions compared with placebo among patients with schizophrenia spectrum disorders receiving antipsychotics, according to a systematic review and network meta-analysis published in JAMA Psychiatry. The analysis also found beneficial effects on other metabolic outcomes with several medications and no major differences between interventions in gastrointestinal adverse effects or study withdrawal.

Researchers conducted a systematic review and frequentist random-effects network meta-analysis of randomized clinical trials evaluating pharmacological interventions for weight reduction in antipsychotic-treated patients with schizophrenia spectrum disorders. They searched Ovid MEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled Trials, CINAHL, ClinicalTrials.gov, and the International Clinical Trials Registry Platform through December 5, 2025, without restricting study duration.

The primary outcome was change in body weight after treatment with a pharmacological intervention compared with placebo or standard care. Secondary outcomes included other anthropometric and metabolic measures. Evidence certainty was assessed using the Confidence in Network Meta-Analysis tool. The initial analysis was conducted from May through November 2025 and updated in December 2025.

Study Findings

The review encompassed 95 studies evaluating 39 pharmacological interventions in a pooled population of 5,898 participants. Compared with placebo, semaglutide was associated with the largest reduction in body weight, with a mean difference of −10.98 kg (95% CI, −13.33 to −8.62; 3 studies; moderate-certainty evidence).

Significant weight reductions were also observed with liraglutide (mean difference, −5.43 kg; 95% CI, −8.54 to −2.33; 2 studies), topiramate (−3.95 kg; 95% CI, −5.89 to −2.02; 5 studies), metformin (−3.86 kg; 95% CI, −5.02 to −2.70; 16 studies), and exenatide (−2.97 kg; 95% CI, −5.83 to −0.11; 3 studies). Evidence certainty was moderate for each intervention. Semaglutide and metformin were associated with clinically meaningful weight reductions of 5% or greater. Ramelteon, nizatidine, and aripiprazole also demonstrated weight-reducing effects, although the certainty of evidence was very low.

Clinical Implications

According to the study authors, adjunctive pharmacological interventions represent an important strategy for addressing weight gain associated with antipsychotic use in schizophrenia spectrum disorders. The findings may help guide clinicians because the magnitude of weight reduction varied substantially among the evaluated medications, with the greatest reductions and highest-certainty evidence reported for semaglutide, liraglutide, topiramate, metformin, and exenatide.

Expert Commentary

“This systematic review and network meta-analysis found substantial variability in weight-related outcomes across pharmacological interventions for antipsychotic-treated individuals with SSDs,” the researchers concluded.

Reference

Stogios N, Agarwal SM, Maksyutynska K, et al. Pharmacological interventions for weight reduction in patients with schizophrenia treated with antipsychotics: a systematic review and network meta-analysis. JAMA Psychiatry. Published online July 8, 2026. doi:10.1001/jamapsychiatry.2026.1814